Decoding antiviral immunity through sorted T cell receptor repertoire sequencing

T cell receptor (TCR) sequencing is an emerging tool in immunovirology with the potential to improve how we detect and interpret virus induced immune responses. This thesis investigates the diagnostic biomarker potential of high-throughput TCR repertoire analysis in two distinct viral contexts: acute SARS-CoV-2 infection and chronic HIV. By using subset-specific TCR sequencing, this work explores how different CD8+ T cell populations could capture temporal dynamics of immune exposure. We demonstrate that activated CD8+ T cells (HLA-DR+/CD38+) are enriched for virus-specific clonotypes during acute infection, enabling discrimination between active COVID-19 and the absence of active infection, including individuals with prior SARS-CoV-2 exposure. In contrast, memory subsets, particularly effector memory cells, retain persistent HIV-specific TCR signatures in people living with HIV (PLWH). These subset-specific profiles reveal a dichotomous model wherein different compartments of the T cell repertoire could serve as indicators of acute or past viral exposure, laying the foundation for a "dual-diagnostic" approach. While promising, the translation of TCR sequencing into clinical diagnostics faces several challenges, including the need for robust, virus-specific TCR signatures, and standardization across genetically diverse populations. Addressing these issues through large-scale, functionally validated, and ethnically diverse cohorts is essential. Ultimately, this thesis establishes that subset-resolved TCR repertoire profiling not only enhances our understanding of viral immunity but could also serve as inspiration for the development of next-generation diagnostics capable of distinguishing between infection stages.